2β-Substituted Analogues of 4‘-Iodococaine:  Synthesis and Dopamine Transporter Binding Potencies

• Published in: Journal of medicinal chemistry 1998-06, Vol.41 (13), p.2380-2389
• Main Authors: Avor, Kwasi S, Singh, Satendra, Seale, Thomas W, Pouw, Buddy, Basmadjian, Garo P
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Drug addictions; Medical sciences; Toxicology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980061w

A series of 2β-substituted analogues of 4‘-iodococaine (3) was synthesized and evaluated in an in vitro dopamine transporter (DAT) binding assay. Selective hydrolysis at the 2β-position of 3 gave the carboxylic acid 15 that served as the intermediate for the synthesis of compounds 4, 5, and 6−11. The 2β-alkyl derivatives were obtained from ecgonine methyl ester (17) through a series of reactions leading to the aldehyde 20. Wittig reaction of 20 with methyltriphenylphosphorane followed by hydrogenation and benzoylation gave the products 12 and 13. The binding affinity of 4‘-iodococaine (3) was 10-fold less than that of cocaine. The hydroxymethane, acetate, amide, benzyl ester, oxidazole, and ethane derivatives of 3 exhibited decreased binding while the vinyl, phenyl, and ethyl esters showed a moderate increase in binding affinity. Only the isopropyl derivative 8 exhibited a 2-fold increase in binding affinity compared with 4‘-iodococaine (3). Hydroxylation of 8 at the 2‘-position gave 14 which enhanced not only the binding potency at the DAT by another 2-fold but also the selectivity at the DAT over the norepinephrine and serotonin transporters. Compound 14 failed to stimulate locomotor activity in C57BL/6J mice over a wide dose range and blocked cocaine-induced locomotor stimulant action.